Diabetic neuropathy is a common complication of diabetes. Early diagnosis is essential if treatment is to be initiated when the disease is most amenable to reversal. Sensitive detection of nerve regeneration is critical for determining the success of a clinical therapeutic trial. Current methods lack the required sensitivity for these tasks. Morphological examination of skin nerves, particularly the nerve fibers in epidermis, relates closely to the degree of neuropathy in diabetic subjects. Reduction of epidermal nerve fibers may be the first morphological sign of diabetic neuropathy. Experimental denervation of epidermal nerves can be produced by topical or intradermal exposure to capsaicin, the active ingredient in hot chili peppers. After discontinuation of capsaicin, nerve regeneration results in recovery. Coincident with capsaicin induced epidermal nerve loss, subjects lost their ability to detect heat pain induced by a 3 mm diameter thermal probe. They recovered hot pain sensitivity when treatment was discontinued. A direct correlation exists between the density of epidermal nerve fibers and ability to detect hot pain in the forearm location studied. However, no change in sensitivity was detected when a larger 30x30 mm commercial probe was used. The small thermal probe holds promise for use as a clinical tool for early diagnosis of neuropathy. The capsaicin model will be used to develop the small probe method for general clinical use. Optimal probe size, temperature setting, and time of heat exposure for skin of different body locations treated with topical capsaicin will be determined in both normal and diabetic subjects. Skin locations that are usually affected by epidermal nerve loss during diabetic neuropathy, e.g. the calf, will receive particular attention. The results will be correlated with counts of epidermal nerve fibers during capsaicin application and during recovery after capsaicin withdrawal. Once the optimal probe size, temperature and exposure are determined the probe will be tested on a cohort of normal and diabetic volunteers to determine the sensitivity of the thermal probe in a clinical setting. The effects of capsaicin on epidermal nerves will be studied by electron microscopy to prove that the loss of nerve fibers seen with immunohistochemical staining methods is indeed the result of destruction of the nerve fibers. This study will develop a small thermal probe for staging neuropathy in a clinical setting, prove that the absence of nerve fibers staining is tantamount to nerve destruction, and demonstrate the capacity for nerve regeneration in subjects with diabetic neuropathy.